Epidemiologic observations in the Boston Early-Onset COPD Study suggest that women may be more susceptible to develop COPD at an earlier age, but the biological basis of gender-specific susceptibility is unknown. Recently, the number of women dying from COPD surpassed the number of men, highlighting the importance of understanding gender-specific factors that may be relevant for COPD susceptibility, diagnosis and treatment. To address a potential biologic explanation, we hypothesize that susceptibility to COPD shares features of susceptibility to autoimmune diseases, and that insight into the variable features of COPD in women versus men may be understood through genetic and epigenetic variation in genes in the human major histocompatibility (MHC) locus and sex-steroid pathway. We will perform extensive genotyping of 2,360 SNPs in 160 genes of the MHC locus in 1,000 family members of the Boston Early-Onset COPD Study, 400 Caucasian COPD cases/400 Caucasian controls and 200 African-American COPD cases/200 African-American controls. We will test for overall association of MHC locus genes with COPD and identify sex-specific associations that replicate between the family-based and case-control analyses. We will also evaluate 384 SNPs in 16 sex-steroid pathway genes for sex-specific associations with COPD in the family- based cohort and attempt replication of findings in the case-control studies. We will explore epistatic interactions between MHC and sex-steroid pathway genes. Although DMA sequence variation is the most common susceptibility factor investigated to understand COPD, epigenetic variation may be important in influencing gene expression. Epigenetic variation through gene methylation has been demonstrated to be important to the sexual dimorphism of common human traits, autoimmune diseases, and lung cancer, but research in COPD has been minimal. In this application, we will evaluate global and specific gene methylation patterns in 371 genes at 1,536 potential methylation sites. We will compare methylation patterns between male and female probands and siblings in the Boston Early-Onset COPD study and male and female COPD cases and controls, to identify genes that may be subject to differential methylation (and potentially sexually dimorphic gene expression in COPD). Thus, genetic and epigenetic hypotheses will be integrated to investigate sex-specific features of COPD.